Neurotrophic substituted pyrimidines

ABSTRACT

The present invention relates to a series of substituted pyrimidines, to pharmaceutical compositions which contain them, to methods for their preparation and to their use in therapy, particularly in the treatment of neurodegenerative or other neurological disorders of the central and peripheral nervous systems.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 national phase application ofInternational Application No. PCT/US00/09108, filed Apr. 6, 2000, whichis a continuation-in-part of U.S. patent application Ser. No.09/288,495, filed Apr. 8, 1999, now U.S. Pat. No. 6,583,148, both ofwhich are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION

The present invention relates to novel derivatives of a series ofsubstituted pyrimidines, to pharmaceutical compositions which containthem, to methods for their preparation and to their use in therapy,particularly in the treatment of neurodegerative or other neurologicaldisorders of the central and peripheral systems including nerveinjuries.

Dementing disorders such as age-related cognitive disorders, e.g.,senility or Alzheimer's disease are medical conditions for which thereare currently only limited therapies. Although studies suggest thatmultiple neurotransmitter systems are involved in senile dementia, aloss of cholinergic neurons and a severe depletion of cholineacetyltransferase appear to show the earliest and strongest correlationswith functional cognitive impairment [see P. T. Francis et al.,Neurochemical Studies of Early-onset Alzheimer's Disease. N. Engl. J.Med., 313, 7 (1985); R. T. Bartus et al., The Cholinergic Hypothesis: AHistorical Overview, Current Perspective, and Future Directions. Ann. N.Y. Acad. Sci., 444, 332 (1985); F. Hefti and L. S. Schneider, NerveGrowth Factor and Alzheimer's Disease, Clin. Neuropharmacol., 14, S62(1991)]. Several groups have attempted to stimulate cholinergic activityby blocking the breakdown of acetylcholine with acetylcholine esteraseinhibitors or by introducing muscarinic or nicotinic agonists [see R. T.Bartus et al., The Cholinergic Hypothesis of Geriatric MemoryDysfunction. Science, 217, 408 (1982); J. Varghese et al., Chapter 21.Alzheimer's Disease: Current Therapeutic Approaches. Annu. Rep. Med.Chem., 28, 197 (1993)]. The approved drugs Cognex and Aricept areacetylcholine esterase inhibitors.

Nerve growth factor (NGF) is the best characterized neurotrophic factorthat is capable of inducing cell differentiation of neural cells andpromoting neurite sprouting. The neurotrophic protein NGF primarilyaffects cholinergic neurons in the central nervous system and may benecessary for their survival [see F. Hefti and P. A. Lapchak,Pharmacology of Nerve Growth Factor in the Brain. Adv. Pharmacol., 24,239 (1993)]. NGF is not systemically bioavailable, but if it is injectedor infused directly into brain, it prevents neuronal cell loss andrestores cognitive function in aged or lesioned rats or monkeys [see W.Fischer et al., NGF Improves Spatial Memory in Aged Rodents as aFunction of Age. J. Neurosci, 11, 1889 (1991)]. NGF effects ultimatelyresult in the stimulation of choline acetyltransferase, the enzyme forbiosynthesis of acetylcholine and the promotion of neurite growth.Consequently, small molecules that produce neurotrophic or “nerve growthfactor-like” (NGF-like) properties in mammalian cell cultures havepotential for use in the treatment of dementing disorders such asage-related senility or Alzheimer's disease and other neurodegenerativeconditions such as peripheral neuropathies, Parkinson's, stroke damage,transient ischemic attacks, trauma-head injuries or other nerveinjuries.

There are several reports of small molecules that exhibit variousaspects of NGF-like activity. Isaxonine [2-(isopropylamino)pyrimidine]was developed as a neurotrophic pharmaceutical but the clinicalapplication was withdrawn, possibly due to toxicological effects [see S.Lehmann et al., Neurite Outgrowth of Neurons of Rat Dorsal Root GangliaInduced by New Neurotrophic Substances with Guanidine Group. Neurosci.Lett., 152, 57 (1993)]. Several 2-(piperazino)pyrimidine derivativeswere reported to possess NGF-like activity and are being studies furtherfor use in treating CNS degenerative diseases [see A. Awaya et al.,Neurotrophic Pyrimidine Heterocyclic Compound. Biol. Pharm. Bull., 16,248 (1993)]. AIT-082(4[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid)is reported to enhance NGF action in cultured PC-12 cells and to restoreage-induced working memory deficits in mice [see P. J. Middlemiss etal., AIT-082, A Unique Purine Derivative, Enhances Nerve Growth FactorMediated Neurite Outgrowth from PC-12 cells. Neuroscience Let., 199, 131(1995)].

The compound SR57746A is reported to have nerve growth factorpotentiating activity and is in clinical trials [see Fournier J, et al.Protective Effects of SR57746A in Central and Peripheral Models ofNeurodegenerative Disorders in Rodents and Primates. Neuroscience,55(3), 629-41, August 1993; U.S. Pat. Nos. 5,270,320 and 5,462,945]. Inaddition, EP0372934, EP0459819 and U.S. Pat. No. 5,075,305 disclosesubstituted pyrimidines having NGF-like properties and its possible usein treating CNS degenerative diseases like Alzheimer's disease as wellas peripheral neuropathies and other peripheral nervous systemdisorders.

SUMMARY OF THE INVENTION

We have now discovered a series of substituted pyrimidines thatdemonstrate NGF-like activity and/or enhancement of NGF activity in PC12cells. The compounds stimulated both neurite outgrowth and cholineacetyltransferase activity in in vitro experiments. Such activities arepredictive for causing increased choline acetyltransferase activity inrat striatum and improving cognitative performance in animal models ofage-induced working memory deficits by potentiating the activity ofendogenous NGF in the brain. [see P. J. Middlemiss et al., AIT-082, AUnique Purine Derivative, Enhances Nerve Growth Factor Mediated NeuriteOutgrowth from PC-12 cells. neuroscience Let., 199, 131 (1995); A. J.Galsky et al., Effect of AIT-082, a Purine Analog, on Working Memory inNormal and Aged Mice. pharmacol. Biochem. Behav., 47, 325 (1994); R.Morris, Developments of a Water-maze Procedure for Studying SpatialLearning in the Rat. J. Neurosci. Methods, 11, 47 (1984)].

DETAILED DESCRIPTION OF THE INVENTION

According to the present invention, there are provided novel compoundsof Formula I:

wherein

W is O, CH2, CH2CH2, OCH2 or CH2CH2CH2;

R₁ is pyrrolidino;

-   -   3-oxopiperidino;    -   4-oxopiperidino; or    -   NR4R5 wherein R4 and R5 are independently H, OH, C3-11alkenyl,        C8-10aryl, C3-11alkynyl, dihydroxyC3-10alkyl, hydroxyC2-10alkyl,        C2-6alkoxy, C6-10aryloxy, C8-10arylC1-6alkoxy,        C1-6alkylthioC2-6alkyl, (C1-6alkyl)j(C3-9cycloalkyl)(CH2)q        (wherein j is 0 or 1 and q is 0-6),        (C1-6alkyl)j(C6-10aryl)(CH2)q (wherein j is 0 or 1 and q is        0-6), (C1-6alkyl)j(C4-9heterocycloalkyl)(CH2)q (wherein j and q        are as above and the heterocyclic ring contains one heteroatom        which is O, S or N), oxo(C3-8cycloalkyl)(CH2)q (wherein q is        0-6), hydroxy(CH2)p(C3-8cycloalkyl)(CH2)q (wherein p and q are        independently 0-6), or C1-8alkyl, provided, however, that both        R4 and R5 are not H, OH or C1-6alkyl, and when R₂ is H and W is        O, neither R4 nor R5 is C1-6alkyl, wherein the C and N atoms of        R4 and R5 may optionally be substituted with one or more        substituents selected from the group consisting of:    -   OH;    -   halogen;    -   thio;    -   thio-oxo;    -   oxo;    -   C1-6alkyl;    -   C2-7alkenyl;    -   C2-7alkynyl;    -   C6-10aryl;    -   C6-10heteroaryl;    -   hydroxyC1-6alkyl;    -   dihydroxyC1-6alkyl;    -   C1-6alkoxy;    -   C1-6aryloxy;    -   C6-10heteroaryloxy;    -   hydroxyC1-6alkoxy;    -   C1-6alkoxyC1-6alkyl;    -   C6-10aryloxyC1-6alkyl;    -   C6-10heteroaryloxyC1-6alkyl;    -   C3-8cycloalkyl;    -   C6-10arylC1-6alkyl;    -   C6-10heteroarylC1-6alkyl;    -   C6-10arylC1-6alkoxy;    -   C6-10heteroarylC1-6alkoxy;    -   C1-6alkylcarbonylC1-6alkyl;    -   C6-10arylcarbonylC1-6alkyl;    -   carboxyC1-6alkyl;    -   C1-6alkoxycarbonylC1-6alkyl;    -   C6-10aryloxycarbonylC1-6alkyl;    -   C6-10arylC1-6alkyloxycarbonylC1-6alkyl;    -   cyanoC1-6alkyl;    -   C1-6alkylthioC1-6alkyl;    -   C1-6alkylsulfinylC1-6alkyl;    -   C1-6alkylsulfonylC1-6alkyl;    -   C6-10arylthioC1-6alkyl;    -   C6-10arylsulfinylC1-6alkyl;    -   C6-10arylsulfonylC1-6alkyl;    -   C6-10arylC1-6alkylthioC1-6alkyl;    -   C6-10arylC1-6alkylsulfinylC1-6alkyl;    -   C6-10arylC1-6alkylsulfonylC1-6alkyl;    -   C6-10heteroarylthioC1-6alkyl;    -   C6-10heteroarylsulfinylC1-6alkyl;    -   C6-10heteroarylsulfonylC1-6alkyl;    -   aziridino;    -   azetidino;    -   pyrrolidino;    -   piperidino;    -   heptamethyleneimino;    -   homopiperazino;    -   N-substituted homopiperazino (wherein the substituent may be        C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);    -   piperazino;    -   N-substituted piperazino (wherein the substituent may be        C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);    -   morpholino;    -   homomorpholino;    -   thiomorpholino;    -   aminoC1-6alkyl;    -   C1-6alkylaminoC1-6alkyl;    -   di(C1-6alkyl)aminoC1-6alkyl (wherein the alkyl groups may be the        same or different);    -   C6-10arylaminoC1-6alkyl;    -   C6-10arylC1-6alkylaminoC1-6alkyl;    -   di(C6-10aryl)aminoC1-6alkyl (wherein the aryl groups may be the        same or different;    -   di(C6-10arylC1-6aryl)aminoC1-6alkyl (wherein the arylalkyl        groups may be the same or different);    -   R12C(O)C1-6alkyl (wherein R12 is aziridino, axetidino,        pyrrolidino, piperidino, heptamethyleneimino, piperazino,        homopiperazino, morpholino, homomorpholino, or thiomorpholino);    -   C(O)R6; (C(O)C(O)R6; C(S)R6; S(O)2R6; and C(NR11)R6 (wherein R11        is hydrogen, C1-6alkyl or C6-10aryl and R6 is H, C1-6alkyl,        C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl);

R₂ is selected from the group consisting of:

-   -   H;    -   NH2, provided that when W is CH2, R₂ is NH2;

R₂ is H;

X is a C8-10 aryl ring or a C6-10 heteroaryl ring optionally substitutedwith one or more substituents Y selected from the group consisting of:

-   -   halogen;    -   C1-6 alkyl;    -   C2-7alkenyl;    -   C2-7alkynyl;    -   C6-10aryl;    -   C6-10heteroaryl;    -   OR;    -   NR8R10 (wherein R8 and R10 may be the same or different and are        H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C8-10arylC1-6alkyl);    -   NROR;    -   C(O)NR9R10;    -   C(O)OR;    -   C(O)R;    -   NRC(O)NR9R10    -   NRC(O)R;    -   NRC(O)OR;    -   CR(OH)R;    -   OC(O)R;    -   S(O)nR wherein R is other than H and n is 0, 1 or 2;    -   NRS(O)mR wherein R is other than H and m is 1 or 2;    -   S(O)2NR9R10;    -   NO2;    -   CN;    -   CF3;    -   OCF3;

R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl; andpharmaceutically acceptable esters, amides, salts or solvates thereof.

The present invention includes all enantiomeric and diastereomeric formsof the compounds of Formula I either individually or admixed in anyproportion.

The present invention further includes prodrugs and active metabolitesof the compounds of Formula I. A prodrug includes any compound which,when administered to a mammal, is converted in whole or in part to acompound of Formula I. An active metabolite is a physiologically activecompound (such as 5-(4-chlorophenoxy)-2,4-diaminopyrimidine) whichresults from the metabolism of a compound of Formula I, or a prodrugthereof, when such compound or prodrug is administered to a mammal.

The compounds of Formula I above and their pharmaceutically acceptableesters, amides, salts or solvates are sometimes hereinafter referred toas “the compounds according to the invention”.

By “alkyl” is meant straight or branched chain alkyl. The alkyl groupsmay be optionally substituted with hydroxy, alkoxy, amino or halogen.

By “aryl” is meant an aromatic ring such as phenyl or naphthyl. The arylgroups may be optionally substituted with hydroxy, alkoxy, amino orhalogen.

By “heteroaryl” is meant a ring containing 1 to 4 heteroatoms selectedfrom the group consisting of N, O and S.

By “halogen” is meant F, Cl, Br or I.

Preferred compounds included in the present invention are moreparticularly defined by the following Formulas IA-IC:

wherein a and b are 0 or 1 and a+b−1; m is 0-2; R₂ is H or NH2, providedthat when a=1, R₂ is NH2; R₁₃ is phenyl, benzyl or cyclohexylsubstituted with 0, 1 or 2 hydroxyl groups; Y is any substituent of X ashereinbefore defined; and pharmaceutically acceptable esters, amides,salts or solvates thereof.

wherein a and b are 0 or 1 and a+b=1; m is 0-2; n is 0-3; R₂ is H orNH2; Y is any substituent of X as hereinbefore defined; and Q isC2-10alkyl optionally substituted with one or more OH; andpharmaceutically acceptable esters, amides, salts or solvates thereof.

Preferred compounds of Formula I are those wherein W is O or CH2 and Xis substituted phenyl; and pharmaceutically acceptable esters, amides,salts or solvates thereof.

Most preferred compounds of Formula I are those wherein R₁ is4-oxocyclohexylamino, trans-4-hydroxycyclohexylamino, 4-hydroxyanilino,or 4-(2-hydroxyethylamino); W is oxygen; X is phenyl optionallysubstituted with 4-chloro, 2,4 dichloro, 4-bromo, 2-fluoro-4-chloro,2-chloro-4-fluoro, 2-methyl-4-chloro, 4-methyl, or 4-ethyl; and R₂ isNH2; and pharmaceutically acceptable esters, amides, salts or solvatesthereof.

Specifically preferred compounds of Formula I are:

-   2-Amino-4-(oxocyclohexylamino)-5-(4-chlorophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(2,4-dichlorophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(4-bromophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(2-fluoro-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(2-chloro-4-(fluorophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(2-methyl-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(4-methylphenoxy)pyrimidine-   2-Amino-4-(oxocyclohexylamino)-5-(4-ethylphenoxy)piperimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(4-chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(2,4-dichlorophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(4-bromophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(2-fluoro-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(2-chloro-4-(fluorophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(2-methyl-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(4-methylphenoxy)pyrimidine-   2-Amino-4-(hydroxycyclohexylamino)-5-(4-ethylphenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(4-chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(2,4-dichlorophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(4-bromophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(2-fluoro-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(2-chloro-4-(fluorophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(2-methyl-4-(chlorophenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(4-methylphenoxy)pyrimidine-   2-Amino-4-(hydroxyanilino)-5-(4-ethylphenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(4-chlorophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(2,4-dichlorophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(4-bromophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(2-fluoro-4-chlorophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(2-chloro-4-fluorophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(2-methyl-4-chlorophenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(4-methylphenoxy)pyrimidine-   2-Amino-4-(2-hydroxyethylamino)-5-(4-ethylphenoxy)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-oxocyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-oxocyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-4-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-4-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-4-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-4-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(2-hydroxyethyl)cyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-4-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-oxocyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-oxocyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(2-hydroxyethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(2-hydroxyethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(2-hydroxyethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(2-hydroxyethyl)cyclopentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclopentylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclopentylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclopentylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclopentylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-(hydroxymethyl)cyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-3-hydroxycyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-hydroxycyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-3-hydroxycyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxymethyl)cyclopropylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(cis-2-(hydroxymethyl)cyclopropylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclopropylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclobutylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclopentylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxycyclohexylmethylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxypropylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxybutylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(5-hydroxypentylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(6-hydroxyhexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-1-methyl)ethylamino))pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1,1-dimethyl-2-hydroxy)ethylamino))pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(1-hydroxymethyl-2-hydroxy(ethylamino))pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-1-hydroxymethyl-1-methyl(ethylamino))pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(tris(hydroxymethyl)methylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2,3-dihydroxypropylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3,4-dihydroxylbutylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(bis(2-hydroxyethyl)amino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(bis(3-hydroxypropyl)amino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)-6-(trifluoromethyl)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxypyrrolidino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxymethylpyrrolidino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxyethylpyrrolidino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-hydroxymethylpyrrolidino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(3-(2-hydroxyethyl)pyrrolidino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(cis-4-hydroxycyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(cis-3-hydroxycyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-4-(hydroxymethyl)cyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclohexylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-3-hydroxycyclopentylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-2-hydroxycyclopentylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-3-(hydroxymethyl)cyclopentylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopentylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(trans-2-(hydroxymethyl)cyclopropylmethylamino)pyrimidine-   5-(4-Chlorophenoxy)-4-(2-hydroxyethylamino)pyrimidine-   5-(4-Ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   5-(2,4-Dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   4-(trans-4-Hydroxycyclohexylamino)-5-(4-trifluoromethylphenoxy)pyrimidine-   5-(4-Chloro-2-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2,4-dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chloro-2-methylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-trifluoromethylphenoxy)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methylphenoxy)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(2-methylphenoxy))pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-isopropylphenoxy)pyrimidine-   2-Amino-5-(4-butylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methoxyphenoxy)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(2-methoxyphenoxy)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-trifluoromethoxy)phenoxy)pyrimidine-   2-Amino-5-(2,3-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2,4-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2,6-difluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chloro-2-fluorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2-chloro-4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(2,4,6-trichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-methylbenzyl)pyrimidine-   2-Amino-5-(4-chlorobenzyl)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(4-trifluoromethylbenzyl)pyrimidine-   2-Amino-4-(trans-4-hydroxycyclohexylamino)-5-(isopropylbenzyl)pyrimidine-   2-Amino-5-(4-chlorobenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(4-bromobenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-4-(4-oxopiperidino)-5-(4-trifluoromethylbenzyl)pyrimidine-   2-Amino-5-(4-methylbenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(4-ethylbenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(4-chlorobenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(4-bromobenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-4-(4-oxopiperidino)-5-(3-trifluoromethylbenzyl)pyrimidine-   2-Amino-5-(4-methylbenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(4-ethylbenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(2,4-dichlorobenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-bromobenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-trifluoromethylbenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-methylbenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-ethylbenzyl)-4-(4-oxopiperidino)pyrimidine-   2-Amino-5-(2,4-dichlorobenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-bromobenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-trifluoromethylbenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-methylbenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(2-chloro-4-ethylbenzyl)-4-(3-oxopiperidino)pyrimidine-   2-Amino-5-(4-chlorophenethyl)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorobenzyloxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-methylanilino)pyrimidine-   4-(4-acetoxyanilino)-2-amino-5-(4-chlorophenoxy)pyrimidine-   2-Amino-5-(4-chlorophenoxy)-4-(2-(2-proprionyloxyethoxy)ethylamino)pyrimidine    hydrochloride-   2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-chloroanilino)pyrimidine-   2-Amino-4-(2-hydroxyethoxyamino)-5-(4-chlorophenyloxy)pyrimidine    and pharmaceutically acceptable esters, amides, salts or solvates    thereof.

In one aspect of the invention there is provided the compounds accordingto the invention for use in medical therapy, particularly for thetreatment of neurodegenerative or neurological disorders of the centralor peripheral nervous systems.

Examples of nervous system disorders which may be treated in accordancewith the invention include dementing disorders such as age-relatedsenility, senile dementia or Age Related Mental Impairment (ARMI),cerebral ataxia, Parkinson's disease, Alzheimer's disease, peripheralneuropathy, cognitive disorders secondary to stroke or trauma andattention-deficit hyperactivity disorder. In addition, nerve injuries,for example, spinal cord injuries, that require neuroregeneration mayalso be treated in accordance with the invention.

In a further aspect of the present invention there is included:

-   a) A method for the treatment of neurodegenerative or neurological    disorders of the central or peripheral nervous systems which    comprises treating the subject e.g., a mammal, such as a human, with    a therapeutically effective amount of a compound according to the    invention.-   b) Use of a compound according to the invention in the manufacture    of a medicament for the treatment of any of the above-mentioned    disorders.

Examples of pharmaceutically acceptable salts of the compounds accordingto the invention include acid addition salts. However, salts ofnon-pharmaceutically acceptable acids may be of utility in thepreparation and purification of the compounds of the invention.

Preferred salts include those formed from hydrochloric, hydrobromic,sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic,succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethansulfonic,p-toluenesulfonic, benzenesulfonic and isethionic acids.

The compounds according to the invention and pharmaceutically acceptableesters, amides, esters, amides, salts or solvates thereof may beemployed in combination with other therapeutic agents for the treatmentof the above disorders. Examples of such further therapeutic agentsinclude Cognex, Aricept and other agents (e.g., acetylcholine esteraseinhibitors, muscarinic or nicotinic receptor agonists, MAO inhibitors)that are effective for the treatment of neurodegenerative orneurological disorders of the central or peripheral nervous systems. Thecomponent compounds of such combination therapy may be administeredsimultaneously in either separate or combines formulations, or atdifferent times, e.g., sequentially such that a combined effect isachieved.

While it is possible for compounds according to the invention to beadministered as the raw chemical, it is preferable to present them as apharmaceutical formulation. The formulations of the present inventioncomprise a compound of Formula I, as above defined, or apharmaceutically acceptable ester, amide, salt or solvate thereof,together with one or more pharmaceutically acceptable carriers thereforand optionally other therapeutic ingredients. The carrier(s) must beacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, transdermal, intradermal, intramuscular and intravenous),rectal and topical (including dermal, buccal and sublingual)administration although the most suitable route may depend upon, forexample, the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well know in the art of pharmacy. All methods includethe step of bringing into association a compound of Formula I or apharmaceutically acceptable ester, amide, salt or solvate thereof(active ingredient) with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately bringing into association the activeingredients with liquid carriers or finely divided solid carriers orboth and then, if necessary, shaping the product into the desiredformulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion, or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacterioistats and solutes which render the formulationisotonic with the blood of the intended recipient; and aqueous andnon-aqueous sterile suspensions which may include suspending agents andthickening agents. The formulations may be presented in unit-dose ormulti-dose containers, for example sealed ampoules and vials, and may bestored in a freeze-dried (lyophillised) condition requiring only theaddition of the sterile liquid carrier, for example,water-for-injection, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets of the kind previously described.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Such patchessuitably contain the active compound 1) in an optionally buffered,aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3)dispersed in a polymer. A suitable concentration of the active compoundis about 1% to 35%, preferably about 3% to 15%. As one particularpossibility, the active compound may be delivered from the patch byelectrotransport or iontophoresis, as generally described inPharmaceutical Res., 3(6), 318 (1986).

Formulations for rectal administration may be presented as suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.Formulations for topical administration in the mouth, for example,buccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbelow recited, or an appropriate fraction thereof, of theactive ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Tablets or other forms of presentation in discrete units mayconveniently contain an amount of compound of the Formula I which iseffective for each of the above-mentioned indications at such dosage oras a multiple of the same, for instance, units containing 5 mg to 500mg, usually between 10 mg to 250 mg.

For the above-mentioned conditions and disorders, the compounds of theFormula I are preferably administered orally or by injection(intraparenteral or subcutaneous). The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. However, the dose employed will depend on a number offactors, including the age and sex of the patient, the precise disorderbeing treated, and its severity. Also the route of administration islikely to vary depending on the condition and its severity.

For each of the above-mentioned indications the compounds of the FormulaI may be administered orally. The dose range for adult humans isgenerally from about 10 to 4000 mg/day and preferably from about 100 to1000 mg/day. It may be advantageous to administer an initial dose of 200to 2000 mg the first day then a lower dose of 100 to 1000 mg onsubsequent days.

For each of the above-mentioned indications, the compounds according tothe invention may be administered by injection at a dose of from about 1to 1000 mg/day, and preferably from about 5 to 1000 mg/day.

The present invention further includes processes for the preparation ofcompounds of Formula (I) and esters, amides, salts or solvates thereof.The compounds of Formula (I) and their esters, amides, salts andsolvates may be prepared in accordance with the present invention by themethods hereinafter describes, or in any manner known in the art for thepreparation of compounds of analogous structure.

By way of illustration, the compounds, esters, amides, salts andsolvates of Formula (I) may be prepared by a process which comprises:

-   -   reacting a compound of Formula (II)        wherein R₂, R₃, W and X are as hereinbefore defined and Z is a        leaving group, with an amine NR′R″ (wherein R′ and R″ are as        defined for R₁) or a suitable derivative thereof. Suitable        leaving groups include halogens such as chlorine. The reaction        is carried out in an organic solvent (e.g., ethanol, propanol,        N,N-dimethylformamide) at a temperature of approximately 20° C.        to approximately 120° C. The compound of Formula (II) may be        isolated and purified prior to reaction with an amine NR′R″ or        may be used in situ.

Compounds of Formula (II) wherein Z is a halogen atom can be preparedfrom compounds of

wherein R₂, R₃, W and X are as hereinbefore defined by reaction with ahalogenating agent (e.g., Vilsmeier reagent (e.g., oxalyl chloride andN,N-dimethylformamide, oxalyl chloride and N,N-diisopropylformamide),phosphorous oxychloride, phosphorous pentachloride, thionyl chloride) ina suitable organic solvent (e.g., dichloromethane, 1,2-dichlorethane,toluene, N,N-dimethlyformamide) at a temperature of approximately 40° C.to approximately 100° C.

Compounds of Formula (III) can be prepared from compounds of Formula(IV)

wherein R₃, W and X are as hereinbefore defined by reaction of analkaline earth salt of (IV) with formamidine or a derivative offormamidine (e.g., guanidine, thiourea, 2-ethyl-2-thiopseudourea) in asuitable organic solvent (e.g., ethanol, methanol, 2-propanol,tert-butanol, tetrahydrofuran) at a temperature of approximately 60° C.to the reflux temperature.

Compounds of Formula (IV) can be prepared from compounds of Formula (V)

wherein W and X are as hereinbefore defined by reaction with an ester(e.g., ethyl formate, ethyl acetate, ethyl benzoate, ethyltrifluoroacetate) and a strong base (e.g., sodium hydride, potassiumhydride, potassium tert-butoxide, sodium metal, lithiumdiisopropylamine) in a suitable organic solvent (e.g., tetrahydrofuran,ether, toluene) at a temperature of approximately 0° C. to approximately40° C.

Compounds of Formula (V) can be prepared by various methods known in theart or are available from commercial sources.

Compounds of Formula (III) wherein R₂ is H can also be prepared fromcompounds of Formula (VI)

wherein R₃, W and X are as hereinbefore defined, by reaction with RaneyNi in a suitable solvent (e.g., ethanol, methanol, 2-methoxyethanol) ata temperature of approximately 60° C. to approximately 100° C.

Specifically preferred intermediate compounds for synthesis of theabove-listed specifically preferred compounds of Formula (I) are:

-   5-(Phenoxy)isocytosine-   5-(4-Methylphenoxy)isocytosine-   5-(4-Chlorophenoxy)isocytosine-   5-(4-Chlorophenoxy)-2-(mercapto)pyrimidin-4-(3H)-one-   5-(4-Chlorobenzyl)isocytosine-   5-(4-Methylbenzyl)isocytosine-   5-(4-Chlorophenoxy)pyrimidin-4(3H)-one-   5-(4-Ethylphenoxy)isocytosine-   5-(4-Chloro-2-fluorophenoxy)isocytosine-   5-(2,4-Dichlorophenoxy)isocytosine-   5-(4-Bromophenoxy)isocytosine-   5-(4-Trifluoromethylphenoxy)isocytosine-   5-(2,4-Difluorophenoxy)isocytosine-   5-(3,4-Difluorophenoxy)isocytosine-   5-(4-Chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidin-4(3H)-one-   5-(4-Chlorophenoxy)-2-(diisopropylaminomethyleneamino)-4-(trans-4-hydroxycyclohexylamino)pyrimidine-   4-Chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine-   5-(2,4-dichlorobenzyl)isocytosine-   5-(2,4,6-trichlorobenzyl)isocytosine-   5-(2,4,6-trichlorophenoxy)isocytosine

Esters and amides of compounds of Formual (I) can be made by reactionwith a carbonylating agent (e.g., ethyl formate, acetic anhydride,methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethylchloroformate, methanesulfonyl chloride) and a suitable base (e.g.,4-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate)in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol,pyridine, N,N-dimethylformamide) at a temperature of 0° C. to 60° C.

Salts of the compounds of Formula (I) can be made from the free baseform by reaction with the appropriate acid.

The following Examples illustrate the present invention but should notbe construed as a limitation to the scope thereof.

Example 1

Preparation of 5-(4-chlorophenoxy)isocytosine

A solution of 4-chlorophenoxyacetic acid (Aldrich) (18.62 g, 99.8mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170mL) was refluxed with stirring under a DRIERITE tube for 96 hours. Thereaction solution was cooled in an ice-bath, and the volatiles wereremoved by spin evaporation in vacuo to a volume of about 100 mL. Theliquid was dissolved in dichloromethane (225 mL) and washed with asolution of 5% aqueous sodium bicarbonate (4×100 mL) and finally withbrine (1×50 mL). The solution was dried over sodium sulfate and spinevaporated in vacuo to give 19.97 g (93% yield) of ethyl4-chlorophenoxyacetate as an amber liquid.

A solution of the ethyl 4-chlorophenoxyacetate (19.90 g, 92.7 mmoles)and ethyl formate (Acros) (30 mL, 371 mmoles) in tetrahydrofuran (100mL) was added dropwise to a stirred dispersion of sodium hydride (60%dispersion in mineral oil) (Aldrich) (5.31 g, 132.7 mmoles) intetrahydrofuran (50 mL). After 30 minutes, when about 60% of thesolution had been added, the reaction was cooled with an ice-bath toslow the reaction. After a total of 1 hour addition was complete, theaddition funnel was rinsed with tetrahydrofuran (15 mL), and thereaction mixture was stirred at ambient temperature for 16 hours. Thesolution was cooled on an ice-bath. The volatiles were removed by spinevaporation in vacuo to give the sodium salt of ethyl2-formyl-2-(4-chlorophenoxy)acetate as a syrup that solidified afterseveral hours. The solid was largely dissolved in ethanol (100 mL) andcombined with a white mixture prepared from mixing sodium methoxide(Aldrich) (6.04 g, 106.2 mmoles) and guanidine carbonate (Aldrich)(10.05 g, 55.7 mmoles) in ethanol (75 mL). The reaction mixture wasrefluxed with stirring for 6 hours. The reaction mixture was cooled onan ice-bath. The volatiles were removed by spin evaporation in vacuo togive a semi-solid residue, which was dissolved in cold water to a volumeof 500 mL. The solution was vigorously stirred and acidified to pH 5with acetic acid (15 mL), which was added in 3 equal portions. The creamcolored mixture was stirred for 2 hours. The solid was collected, washedextensively with water (750 mL), and vacuum suction air dried to givethe crude solid. The solid was heated with stirring in ethanol to afinal volume of 200 mL. The cooled mixture was collected, washed withethanol and dried to give 16.83 g (76% yield) of5-(4-chlorophenoxy)isocytosine as a white solid, mp 245° C.

Example 2

Preparation of4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine

Diisopropylformamide (Aldrich) (92.56 g, 0.716 mole) and dichloromethane(mL) were combined in a 5 L three-neck round bottom flask equipped withan air stirrer, reflux condenser, thermometer and dropping funnel withdrying tube. Neat oxalyl chloride (Aldrich) (100 g, 0.788 mole) wasslowly added over 3 hours during which the reaction temperature remainedat 22-25° C. Solid 5-(4-chlorophenoxy)isocytosine (65.68 g, 0.276 mole)was added, and the mixture was refluxed for 2.5 hours to give a clearburgundy colored solution. After cooling to ambient temperature, a coldsolution of saturated aqueous sodium bicarbonate solution (1.1 L) wasadded in 15-20 mL increments with rapid stirring. The organic phase wasseparated, washed with water (1×1 L), saturated brine (1×1 L) and driedover sodium sulfate. This solution was filtered through a bed of SilicaGel (150 g; 4×26 cm) in dichloromethane, and the bed was rinsed withadditional dichloromethane (500 mL). The combined filtrates and washingswere evaporated in vacuo to a thick oil, which was immediately stirredwith hexanes (1.5 L) to give a flocculent white solid. The solids werecollected, rinsed with hexanes and dried in vacuo at ambient temperatureto give 77.3 g (76% yield) of4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidineas white needles, mp 135-136° C.

Example 3

Preparation of2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine

4-Chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine(3.68 g, 0.01 mole) and trans-4-aminocyclohexanol hydrochloride (5.31 g,0.035 mole) were combined in absolute ethanol (25 mL). Triethylamine(7.08 g, 0.07 mole) was added, and the mixture was refluxed withstirring for 56 hours when thin layer chromatography confirmed theabsence of the starting pyrimidine. The mixture was cooled slightly,concentrated hydrochloric acid (5 mL) was added and reflux was resumedfor an additional 2 hours. The mixture was spin evaporated in vacuo. Theoily residue was dissolved in water (200 mL) and extracted withdichloromethane (2×200 mL). The aqueous phase was basified with 2 Msodium hydroxide to pH 9, and the gummy residue that precipitated wasdissolved in dichloromethane (100 mL). The aqueous phase was back washedwith dichloromethane (100 mL), and the combined organic extracts werewashed with brine (200 mL), dried over sodium sulfate, filtered and spinevaporated in vacuo to a foam. This material was dissolved in ethylacetate and chromatographed on Silica Gel 60 (E. M. Science, 230-440mesh) (8 g; 2×7 cm column bed) using ethyl acetate as eluent. The first100 mL of eluent was collected and spin evaporated in vacuo to give 2.30g (69% yield) of2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidineas a white powder, mp 154-155° C.

Example 4

Preparation of2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride

Chromatographically pure2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine(0.93 g, 2.78 mmoles) was dissolved in ethanol (10 mL), concentratedhydrochloric acid (1 mL) was added, and the solution was spin evaporatedin vacuo to give a solid. The solid was triturated under ethyl acetateto give a white solid which was collected, washed with ethyl acetate anddried in vacuo to give 0.93 g (90% yield) of2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride as white crystals, mp 155-156° C.

Example 5

Preparation of2-amino-5-(2,4-dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride

A solution of oxalyl chloride (Aldrich) (3.91 g, 30.19 mmoles) indichloromethane (5 mL) was added in several portions to a stirred,ice-bath cooled solution of diisopropylformamide (Aldrich) (4.09 g,31.02 mmoles) in dichloromethane (100 mL). The ice-bath was removed, andthe clear solution was stirred at ambient temperature for 15 minutes.Solid 5-(2,4-dichlorophenoxy)-isocytosine (2,24 g, 8.23 mmoles) wasadded, and the mixture was refluxed with stirring for 0.5 hour. Theresultant solution was cooled and poured into a cold solution ofvigorous stirred, saturated aqueous sodium bicarbonate (150 mL). Thelayers were separated, and the organic phase was washed with coldsaturated aqueous sodium bicarbonate (100 mL), with cold water (100 mL)and then dried over sodium sulfate. The dry solution was spin evaporatedin vacuo to give the intermediate4-chloro-5-(2,4-dichlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidineas a syrup. The syrup was dissolved in ethanol (100 mL) andtrans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (4.97 g, 31.79mmoles) was added. A solution of sodium ethoxide, which has beenprepared from sodium hydride (60% in mineral oil) (Aldrich) (1.19 g,29.75 mmoles) and ethanol (25 mL) was added, and the reaction wasrefluxed with stirring for 66 hours. Concentrated hydrochloric acid (21mL) was added to the cooled reaction mixture, and the reaction wasrefluxed with stirring for 4 hours. The volatiles were removed by spinevaporation in vacuo. The residue was dissolved in water (200 mL) andextracted with dichloromethane (3×80 mL). The pH of the aqueous solutionwas adjusted to 8 with 2 M sodium hydroxide. The gummy residue thatprecipitated was dissolved in dichloromethane (100 mL). The aqueousphase was extracted with dichloromethane (100 mL), and the combinedorganic extracts were washed with water (5×80 mL), dried over sodiumsulfate and spin evaporated in vacuo to a foam. This material wasdissolved in ethyl acetate and chromatographed on Silica Gel 60 (E. M.Science, 230-440 mesh) (12×4 cm column bed) using ethyl acetate as theeluent for the first 750 mL and then with 5% ethanol in ethyl acetate.The fractions that contained homogeneous product were spin evaporated invacuo to give a syrup. The pure2-amino-5-(2,4-dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinewas converted to the hydrochloride by the same procedure described inExample 4. Repeated spin evaporation of the residue under ethanol, thanethyl acetate and finally hexanes gave 1.42 g (42% yield) of2-amino-5-(2,4-dichlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride as a fluffy solid, mp 138-145° C.

Example 6

Preparation of ethyl 4-ethylphenoxyacetate

A mixture of 4-ethylphenol (Aldrich) (14.34 g, 116.20 mmoles), anhydrouspotassium carbonate (Aldrich) (20.47 g, 146.63 mmoles), ethylbromoacetate (Aldrich) (17.01 g, 99.81 mmoles) and dry acetone (Aldrich)(200 mL) was refluxed with stirring under a drying tube for 18 hours.The reaction was cooled, and the volatiles were removed by spinevaporation in vacuo. The white residue was partitioned between ice-coldwater (250 mL) and dichloromethane (250 mL). The dichloromethane phasewas separated and washed with ice cold water (2×100 mL), an ice-coldsolution of 5% aqueous sodium hydroxide (150 mL) and finally withice-cold water (2×100 mL). The dichloromethane solution was dried oversodium sulfate and spin evaporated in vacuo to give 19.86 g (95% yield)of ethyl 4-ethylphenoxyacetate as a clear liquid, which was one spot onthin layer chromatography.

Example 7

Preparation of 5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one

A solution of ethyl 4-ethylphenoxyacetate (19.85 g, 95.31 mmoles) andethyl formate (Acros) (35 mL, 433.25 mmoles) in tetrahydrofuran (100 mL)was added dropwise to a stirred dispersion of sodium hydride (60%dispersion in mineral oil) (Aldrich) (5.53 g, 138.25 mmoles) intetrahydrofuran (50 mL). After 30 minutes, when about 60% of thesolution had been added, the reaction was cooled with an ice-bath toslow the reaction. After a total of 1 hour addition was complete, theaddition funnel was rinsed with tetrahydrofuran (15 mL), and thereaction mixture was stirred at ambient temperature for 20 hours. Thesolution was cooled on an ice-bath. The volatiles were removed by spinevaporation in vacuo to give the sodium salt of ethyl2-formyl-2-(4-ethylphenoxy)acetate as a brown semisolid. The semisolidwas largely dissolved in ethanol (200 mL) and combined with thiourea(Aldrich) (8.79 g, 114.32 mmoles). The reaction mixture was refluxedwith stirring for 22 hours and then cooled on an ice-bath. The volatileswere removed by spin evaporation in vacuo to give a semi-solid residue,which was dissolved in water to a volume of 500 mL in a 1.5 L beaker.The solution was covered with hexanes (200 mL) and vigorously stirred.The hexanes layer was decanted and discarded. The hexanes wash procedurewas repeated three times. Some insoluble material was removed from theaqueous solution by filtration through flutted filter paper. Thefiltrate was cooled and acidified by the rapid, dropwise addition of adilute hydrochloric acid solution (prepared from concentratedhydrochloric acid (12 mL) and water (50 mL)) to the stirred filtrate.Additional water (300 mL) was added during acidification to facilitatestirring. The cream colored solid was collected, washed extensively withwater (1800 mL), and vacuum suction air dried to give the crude product.The solid was heated with stirring in hexanes to a final volume of 400mL. The cooled mixture was collected, washed with hexanes and dried togive 13.00 g (52% yield)5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one as a white solid,mp >220° C. Recrystallization of a sample from hexanes-ethyl acetategave analytically pure5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one as a white powder,mp 242-244° C.

Example 8

Preparation of 5-(4-ethylphenoxy)pyrimidine-4(3H)-one

A mixture of 5-(4-ethylphenoxy)-2-(mercapto)pyrimidine-4(3H)-one (2.49g, 10.28 mmoles), ethanol (250 mL) and wet Raney Ni (50% slurry inwater, active catalyst) (Aldrich) (10.9 g) was refluxed with stirringfor 3 hours. The reaction was cooled to about 40° C. and filteredthrough a pad of CELITE 545 (Fisher). The pad was washed with hotethanol (2×75 mL) and placed in a beaker of water. The combinedfiltrates were spin evaporated in vacuo to a syrup. The syrup wasdissolved in ethyl acetate and reevaporated to give a gray solid. Thesolid was dissolved in ethyl acetate (40 mL) and applied to a column(4.2×9.5 cm) of Silica Gel 60 (E. M. Science, 230-440 mesh) that wasequilibrated with ethyl acetate. The column was eluted with ethylacetate by flash chromatography, and twelve 100 mL fractions werecollected. Fractions 4-10 were combined and spin evaporated in vacuo.The residual oil was dissolved in ethyl acetate and evaporated to give amixture of light green and white crystals. The crystals were dissolvedin dichloromethane and spin evaporated in vacuo to give 1.37 g (63%yield) of 5-(4-ethylphenoxy)pyrimidine-4(3H)-one. Recrystallization of asample from ethyl acetate gave analytically pure5-(4-ethylphenoxy)pyrimidine-4(3H)-one as white needles, mp 144-146° C.

Example 9

Preparation of5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride

A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) indichloromethane (6 mL) was added in several portions to a stirred,ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g,15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, andthe solution was stirred at ambient temperature for 10 minutes. Solid5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added,and the mixture was refluxed with stirring for 45 minutes. The solutionwas cooled and poured into a cold solution of vigorously stirred,saturated aqueous sodium bicarbonate (80 mL). The organic layer waswashed with cold saturated aqueous sodium bicarbonate (80 mL), with coldwater (80 mL) and then dried over sodium sulfate. The dry solution wasspin evaporated in vacuo to give the intermediate4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquidwas dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylaminehydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution ofsodium ethoxide, which had been prepared from sodium hydride (60% inmineral oil) (Aldrich) (0.41 g, 10.25 mmoles) and ethanol (15 mL) wasadded. The flask was rinsed with ethanol (10 mL), and the reaction wasrefluxed with stirring for 65 hours. The volatiles were removed by spinevaporate in vacuo to a small volume, and the residue was trituratedwith water (100 mL). The gummy residue was extracted withdichloromethane (150 mL). The solution was washed with water (80 mL),dried over sodium sulfate and spin evaporated in vacuo. This materialwas dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel60 (E. M. Science, 230-440 mesh) (13×4 cm column bed) using ethylacetate as the eluent for the first 1.2 L and then with 5% ethanol inethyl acetate. The fractions that contained homogeneous product werespin evaporated in vacuo to give a syrup. The pure5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine wasconverted to the hydrochloride by the same procedure described inExample 4. The residue was triturated under ethyl acetate to give awhite solid which was collected, washed with ethyl acetate and dried invacuo to give 1.25 g (77% yield) of5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidinehydrochloride as a white solid, mp 245-243° C.

Example 10

Preparation of a2-amino-5-(4-chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidinehydrochloride

Acetic anhydride (0.61 g, 5.8 mmoles) and pyridine (0.96 g, 11.9 mmoles)were added to an ice-bath cooled suspension of chromium(IV) oxide(Aldrich) (0.61 g, 6.1 mmoles) in dichloromethane (11 mL). The mixturewas stirred at ambient temperature for 20 minutes, and2-amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine(0.65 g, 1.87 mmoles) was added, followed by dichloromethane (10 mL).The mixture was stirred for 1.25 hours and poured into cold ethylacetate (200 mL), stirred for 15 minutes and filtered through a pad ofCELITE 545 (Fisher). The filtrate was filtered through flutted filterpaper and then spin evaporated in vacuo. The residue was purified byflash column chromatography on Silica Gel 60 (E. M. Science, 230-440mesh) (2×16 cm) using ethyl acetate as the eluant. The fractions thatcontained homogeneous product were spin evaporated in vacuo to give asyrup. The flash column chromatography was repeated. The pure2-amino-5-(4-chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidine wasconverted to the hydrochloride by the same procedure described inExample 4. The residue was triturated under ethyl acetate to give awhite solid which was collected, washed with ethyl acetate and dried invacuo to give 0.29 g (41% yield) of2-amino-5-(4-chlorophenoxy)-4-(4-oxocyclohexylamino)pyrimidinehydrochloride as a white solid. [Method modeled after M. J. Robins etal. J. Med. Chem., 35, 2283-2293 (1992)]

Example 11

Preparation of2-amino-5-(4-chlorophenoxy)-4-(4-hydroxyanilino)pyrimidine hydrochloride

Nitrogen was bubbled through a suspension of 10.11 g (27.5 mmol) of4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine(see Example 2) in 205 ml of methanol for 10 minutes. Then 3.18 g (29.1mmol) of 4-aminophenol was added and nitrogen bubbled through thesuspension for 5 minutes. The solution was then tightly sealed andstirred at 24° C. for 20 hours. Then 50 ml of concentrated hydrochloricacid was added to the mixture and refluxed for 140 minutes. The mixturewas cooled and spin evaporated to one-half the original volume and thenstored at 3° C. After 3 hours, a large precipitate had formed which wascollected by filtration and washed quickly with cold methanol. Thefilter cake was suspended in 79 ml of CH₂Cl₂ and the suspension wasboiled for 5 minutes. The solids were collected by filtration, washedwith CH₂Cl₂ and dried in vacuo at 100° C. 8.6 g (86%) of product as apale yellow powder was obtained, mp 288-289° C.

Example 12

Preparation of2-amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-methylanilino)pyrimidine

Nitrogen was bubbled through a suspension of 2 g (9 mmol) of4-chloro-5-(4-chlorophenoxy)-2-(diisopropylaminomethyleneamino)pyrimidine(see Example 2) in 20 ml of ethanol for 10 minutes. Then 1.15 g (9.34mmol) of 4-amino-3-methylphenol was added and nitrogen bubbled throughthe suspension for 5 minutes. The solution was then tightly sealed andstirred at 24° C. for 20 hours. Then 5 ml of concentrated hydrochloricacid was added to the mixture and refluxed for 60 minutes. The mixturewas cooled and spin evaporated. The residue was suspended in 100 mLCH₂Cl₂ and 400 mL water. The pH was adjusted to 12 with 3N NaOH. Theorganic phase was washed with water (400 mL) twice, brine (200 mL) andthen dried over Na₂SO₄. The salt was removed by filtration and thefiltrate applied to a Silica Gel 60 column (2.5×10 cm) preequilibratedwith CH₂Cl₂. The column was eluted with 800 mL CH₂Cl₂ and then withmixtures of ethylacetate and CH₂Cl₂. The fractions showing one spot onTLC (EtOAc; Rf0.45) were pooled and concentrated by spin evaporation.The liquor formed crystals on standing. 0.19 g (6% yield) of product, awhite solid, was obtained after drying in vacuo at 105° C. for 16 hours,mp 199-201° C.

Example 13

Preparation of4-(4-acetoxyanilino)-2-amino-5-(4-chlorophenoxy)pyrimidine

1.26 g (3.45 mmoles) of2-amino-5-(4-chlorophenoxy)-4-(4-hydroxyanilino)pyrimidine hydrochloride(see Example 11) and 0.05 g of 4-dimethylaminopyridine were dissolved in3.2 g of dry N,N-dimethylformamide. 5.3 g of acetic anhydride was added,and the container was sealed. After 5 days at 24° C., 100 mL of CH₂Cl₂were added to the reaction mixture and stirred with 150 mL of coldsaturated aqueous NaHCO₃. The organic layer was then washed twice with250 mL of water, then with 200 mL of brine and dried over Na₂SO₄. Afterfiltering off the salt, the filtrate was applied to a Silica Gel 60column (2.5×7.5 cm) which had been preequalibrated with hexanes. Thecolumn was eluted with 200 mL hexanes, a mixture of 100 mL hexanes and200 mL CH₂Cl₂, and 500 mL CH₂Cl₂. Fractions with product which was pureby TLC (EtOAc; Rf 0.6) were pooled and spin evaporated to a waxy solid.This solid was removed from the flask with the aid of hot hexanes. Aftercooling, solids were collected by filtration and washed with hexanes.After drying in vacuo at 89° C. for 16 hours, the product, a creamcolored powder, 0.14 g (11% yield), was obtained, mp 132-133° C.

The following additional compounds of the present invention wereprepared by methods analogous to those described above:

Chemical Name MP° C.2-Amino-5-(4-chlorophenoxy)-4-(trans-4-hydroxycyclohexyl- 155-156amino)pyrimidine.HCl2-Amino-5-(4-chlorophenoxy)-4-(trans-2-hydroxycyclohexyl- 175-180amino)pyrimidine.HCl2-Amino-5-(4-chlorophenoxy)-4-(cyclohexylamino)pyrimidine 90-952-Amino-5-(4-chlorophenoxy)-4-(2-hydroxyethylamino)- 154-155 pyrimidine2-Amino-5-(4-chlorophenoxy)-(4-hydroxypentylamino)- 160-161 pyrimidine2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-1-methyl(ethyl- 193-194amino))pyrimidine 2-Amino-5-(4-chlorophenoxy)-4-(1,1-dimethyl-2- 142-143hydroxyethylamino)pyrimidine2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxypropylamino)- 138-140pyrimidine.HCl 2-Amino-5-(4-chlorophenoxy)-4-(1-ethyl-2- 88-90hydroxyethylamino)pyrimidine.HCl2-Amino-5-(4-chlorophenoxy)-4-bis(2-hydroxyethyl)amino) 148-150pyrimidine 2-Amino-5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexyl-245-253 amino)pyrimidine.HCl2-Amino-5-(4-chlorobenzyl)-4-(trans-4-hydroxycyclohexyl- 85-87amino)pyrimidine2-Amino-5-(4-chlorophenoxy)-4-(2-(2-proprionyloxyethoxy)  99-100ethylamino)pyrimidine hydrochloride2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-chloroanilino) 225 pyrimidine2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-3-chloroanilino) 221 pyrimidine

The following examples illustrate representative pharmaceuticalcompositions where the “Active Ingredient” may be any compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Example A—Tablet Composition

mg/tablet (a) Active Ingredient 250 (b) Lactose B.P. 210 (c) PovidoneB.P. 15 (d) Sodium Starch Glycollate 20 (e) Magnesium Stearate 5

The composition is prepared by wet granulation of the ingredients with asolution of povidone, followed by addition of magnesium stearate andcompression.

Example B—Capsule Composition

A capsule composition is prepared by admixing the ingredients andfilling into a two-part hard gelatin capsule.

mg/capsule (a) Active Ingredient 250 (b) Lactose B.P. 143 (c) SodiumStarch Glycollate 25 (d) Magnesium Stearate 2

Example C—Injectable Composition

(a) Active Ingredient 0.200 g (b) Hydrochloric Acid Solution 0.1 M or4.0 to 7.0 Sodium Hydroxide Solution 0.1 M to a pH of: (c) Sterile Waterq.s. to: 10 ml

The active ingredient is dissolved in most of the water (35°-40° C.) andthe pH is adjusted to between 4.0 and 7.0. The batch is then made up tovolume with sterile water and filtered through a sterile microporefilter into a sterile amber glass vial (type 1) and sealed with sterileclosures and overseals.

The compounds of the present invention were assayed for neurotrophicactivity as follows:

A. Screen for NGF-like Activity:

Cultured PC12 cells (rat adrenal pheochromocytoma from ATCC) havereceptors for NGF. Responses include promotion of neurite outgrowth andelevation of choline acetyltransferase (ChAT) (L. A. Green and A. S.Tischler, Cell Neurobiol., 3, 373 (1982)).

The following assay is modified from that described in H L White and P WScates, Neurochem. Res., 16, 63 (1991). PC12 cells were cultured at 37°C. in RPMI supplemented with HEPES buffer, pH 7.5 (to 10 mM), fetalbovine serum, horse serum, glutamine, penicillin, streptomycin andnon-essential amino acids. Cultures were split 1:3 every 3 to 4 days.Exponentially dividing cells were plated into fresh medium oncollagen-coated 12-well plastic dishes (10⁵ cells/well). After allowingone day for cell attachment, the medium was replaced with low serummedium, with or without test compounds with each condition intriplicate. The medium may contain up to 0.2% ethanol, which was used asa solvent for most compounds tested. Cells were examined formorphological changes using an Olympus IMT-2 inverted researchmicroscope. After 3 days incubation with test compounds, medium wasremoved and replaced with 0.2 ml of lysis and ChAT assay mixture. Theplates were incubated at 37° C. for 2 hours and then placed into afreezer at −20° C.

Compounds are judged NGF-like in this primary screen if they (1)increase the activity of ChAT, (2) enhance NGF-stimulated neuriteoutgrowth or (3) potentiate or appear additive with the action of NGFitself.

B. Choline Acetyltransferase (ChAT) Assays:

The assay mixture contained 100 mM phosphate, pH 7.4, 0.1% NP-40, 150 mMNaCl, 1.5 mM choline, 10 mM EDTA, 0.1 mM eserine, 0.1 mM acetyl-coenzymeA and about 0.5 uCi (40-70 Ci/mol) [14C]acetyl-coenzyme A in each ml ofmixture. Thawed and lysed cell reaction mixtures were diluted to 1 mlwith water and transferred to 7 ml scintillation vials containing 5 mlof extraction/scintillation fluid solution (50 mg triphenyl borate, 50mg PPO, 20 mg POPOP per 100 ml of 20% acetonitrile/80% toluene) andvortexed for 10 seconds. After all diluted well contents weretransferred and mixed, all the vials were vortexed again for 30 seconds,rotated for about 2 hours, and then vortexed once more. The vials werecentrifuged at 3000 rpm (max.=16 cm) for 15 minutes and then counted ina Beckman LS6500 scintillation counter. Background counts from reactionmixtures with extracts from nonstimulated cells (no NGF and no testcompound) were subtracted from reaction product counts beforecomparisons of ChAT activities were made.

The following data were obtained for representative compounds of thepresent invention which (1) increased the activity of cholineacetyltransferase ChAT), (2) enhanced NGF-stimulated neurite outgrowthand/or (3) potentiated or appeared additive with the action of NGFitself. The concentration at which the test compound doubled the ChATactivity over the activity with NGF alone (no test compound) wasrecorded as the EC_(2x) value:

Compound of EC_(2x) (uM) Example 3 0.4 Example 5 1.2 Example 10 0.7

1. A compound of the formula

wherein W is O, CH₂, CH₂CH₂, OCH₂ or CH₂CH₂CH₂; R₁ is NR₄R₅ wherein R₄ and R₅ are independently H, OH, C6-10aryl, C2-6alkoxy, C6-10aryloxy, or (C1-6alkyl)j(C6-10aryl)(CH₂)q (wherein J is 0 or 1 and q is 0-6), provided that when R₄ is H or OH, then R₅ is not H or OH, and wherein the C atoms of R₄ and R₅ may optionally be substituted with one or more substituents selected from the group consisting of: OH; halogen; thio; thio-oxo; oxo; C1-6alkyl; C2-7alkenyl; C2-7alkynyl; C6-10aryl; C6-10heteroaryl; hydroxyC1-6alkyl; dihydroxyC1-6alkyl; C1-6alkoxy; C1-6aryloxy; C6-10heteroaryloxy; hydroxyC1-6alkoxy; C1-6alkoxyC1-6alkyl; C6-10aryloxyC1-6alkyl; C6-10heteroaryloxyC1-6alkyl; C3-8cycloalkyl; C6-10arylC1-6alkyl; C6-10arylC1-6alkoxy; C6-10heteroarylC1-6alkoxy; C1-6alkylcarbonylC1-6alkyl; C6-10arylcarbonylC1-6alkyl; carboxyC1-6alkyl; C1-6alkoxycarbonylC1-6alkyl; C6-10aryloxycarbonylC1-6alkyl; C6-10arylC1-6alkyloxycarbonylC1-6alkyl; cyanoC1-6alkyl; C1-6alkylthioC1-6alkyl; C1-6alkylsulfinylC1-6alkyl; C1-6alkylsulfonylC1-6alkyl; C6-10arylthioC1-6alkyl; C6-10arylsulfinylC1-6alkyl; C6-10arylsulfonylC1-6alkyl; C6-10arylC1-6alkylthioC1-6alkyl; C6-10arylC1-6alkylsulfinylC1-6alkyl; C6-10arylC1-6alkylfulfonylC1-6alkyl; C6-10heteroarylthioC1-6alkyl; C6-10heteroarylsulfinylC1-6alkyl; C6-10heteroarylsulfonylC1-6alkyl; aziridino; azetidino; pyrrolidino; piperidino; heptamethyleneimino; homopiperazino; N-substituted homopiperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl); piperazino; N-substituted piperazino (wherein the substituent may be C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl); morpholino; homomprpholino; thiomorpholino; aminoC1-6alkyl; C1-6alkylaminoC1-6alkyl; di(C1-6alkyl)aminoC1-6alkyl (wherein the alkyl groups may be the same or different); C6-10arylaminoC1-6alkyl; C6-10arylC1-6alkylaminoC1-6alkyl; di(C6-10aryl)aminoC1-6alkyl (wherein the aryl groups may be the same or different); di(C6-10arylC1-6alkyl)aminoC1-6alkyl (wherein the arylalkyl groups may be the same or different); R₁₂C(O)C1-6alkyl (wherein R₁₂ is aziridino, azetidino, pyrrolidino, piperidino, heptamethyleneimino, piperazino, homopiperazino, morpholino, homomorpholine, or thiomorpholino); C(O)R₆; C(O)C(O)R₆; C(S)R₆; S(O)₂R₆; and C(NR₁₁)R₆ (wherein R₁₁ is H, C1-6alkyl or C6-10aryl and R₆ is H, C1-6alkyl, C1-6alkyl, C6-10aryl, C6-10arylC1-6alkyl or C6-10heteroaryl); R₂ is H or NH₂, provided that when W is CH₂, then R₂ is NH₂; X is a C6-10 aryl ring or a C6-10 heteroaryl ring optionally substituted with one or more substituents Y selected from the group consisting of: halogen; C1-6 alkyl; C2-7alkenyl; C2-7alkynyl; C6-10aryl; C6-10heteroaryl; OR (wherein R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl); NR₉R₁₀ (wherein R₉ and R₁₀ may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl); NROR; C(O)NR₉R₁₀; C(O)OR; C(O)R; NRC(O)NR₉R₁₀; NRC(O)R; NRC(O)OR; CR(OH)R; OC(O)R; S(O)nR′ (wherein R′ is C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl and n is 0, 1 or 2); NRS(O)mR′ (wherein m is 1 or 2); S(O)₂NR₉R₁₀; NO₂; CN; CF₃; and OCF₃; wherein each C6-10heteroaryl group is an aryl ring having 1 to 4 carbon atoms replaced by heteroatoms selected from the group consisting of N, O and S; or a pharmaceutically acceptable ester, amide or salt thereof.
 2. A compound according to claim 1, wherein W is O or CH₂ and X is substituted phenyl.
 3. A compound according to claim 1, wherein R₁ is 4-hydroxyanilino or 4-hydroxybenzylamino; W is O; X is phenyl optionally substituted with 4-chloro, 2,4-dichloro, 4-bromo, 2-fluoro-4-chloro, 2-chloro-4-fluoro, 2-methyl-4-chloro, 4-methyl, or 4-ethyl; and R₂ is NH₂.
 4. A compound of the formula

wherein a and b are 0 or 1 and a+b=1; m is 0−2; R₂ is H or NH₂, provided that when a is 1, then R₂ is NH₂; R₁₃ is phenyl or benzyl optionally substituted with up to three substituents selected from the group consisting of: OH; halogen; C1-6alkyl; hydroxyC1-6alkyl; dihydroxyC1-6alkyl; C1-6alkoxy; hydroxyC1-6alkoxy; C1-6alkoxyC1-6alkyl, and carboxyC1-6alkyl; and each Y is selected from the group consisting of: halogen; C1-6 alkyl; C2-7alkenyl; C2-7alkynyl; C6-10aryl; C6-10heteroaryl; OR (wherein R is H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl); NR₉R₁₀ (wherein R₉ and R₁₀ may be the same or different and are H, C1-6alkyl, C3-8cycloalkyl, C6-10aryl, or C6-10arylC1-6alkyl); NROR; C(O)NR₉R₁₀; C(O)OR; C(O)R; NRC(O)NR₉R₁₀ NRC(O)R; NRC(O)OR; CR(OH)R; OC(O)R; S(O)nR′ (wherein R′ is C1-6alkyl, C3-8cycloalkyl, C6-10aryl or C6-10arylC1-6alkyl and n is 0, 1 or 2); NRS(O)mR′ (wherein m is 1 or 2); S(O)₂NR₉R₁₀; NO₂; CN; CF₃; and OCF₃; wherein each C6-10heteroaryl group is an aryl ring having 1 to 4 carbon atoms replaced by heteroatoms selected from the group consisting of N, O and S; or a pharmaceutically acceptable ester, amide or salt thereof.
 5. A compound according to claim 4, wherein R₁₃ is phenyl substituted with 1 or 2 hydroxyl groups.
 6. A compound according to claim 4, wherein R₁₃ is benzyl substituted with 1 or 2 hydroxyl groups.
 7. A compound selected from the group consisting of: 2-Amino-4-(4-hydroxyanilino)-5-(4-chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(2,4-dichlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-bromophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(2-fluoro-4-(chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(2-chloro-4-(fluorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(2-methyl-4-(chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-methylphenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-ethylphenoxy)pyrimidine; 2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-methylanilino)pyrimidine; 2-Amino-5-(4-chlorophenoxy)-4-(2-hydroxy-4-methylanilino)pyrimidine; 4-(4-Acetoxyanilino)-2-amino-5-(4-chlorophenoxy)pyrimidine; 2-Amino-5-(4-chlorophenoxy)-4-(2-(2-proprionyloxyethoxy)ethylamino) pyrimidine hydrochloride; 2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-2-chloroanilino)pyrimidine; 2-Amino-5-(4-chlorophenoxy)-4-(4-hydroxy-3-chloroanilino)pyrimidine; 2-Amino-4-(methoxyamino)-5-(4-chlorophenyloxy)pyrimidine; 2-Amino-4-(2-hydroxyethoxyamino)-5-(4-chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-phenoxypyrimidine; 2-Amino-4-(4-hydroxy-2-methylanilino)-5-phenoxypyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(2-chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydorxy-2-methylanilino)-5-(2-chlorophenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine; 2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-chloro-2-methylphenoxy)pyrimidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-butylphenoxy)pyrimidine; 2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-butylphenoxy)piperidine; 2-Amino-4-(4-hydroxyanilino)-5-(4-methoxyphenoxy)pyrimidine; 2-Amino-4-(4-hydroxy-2-methylanilino)-5-(4-methoxyphenoxy)pyrimidine; and 2-Amino-4-(4-hydroxy-2-methylanilino)-5-(2-methoxyphenoxy)pyrimidine.
 8. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier therefor.
 9. A pharmaceutical composition, comprising a compound according to claim 4 and a pharmaceutically acceptable carrier therefor.
 10. A pharmaceutical composition, comprising a compound according to claim 7 and a pharmaceutically acceptable carrier therefor.
 11. A method of treating a mammal having a neurodegerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim
 1. 12. A method according to claim 11, wherein the disorder is a dementing disorder.
 13. A method according to claim 12, wherein the disorder is Alzheimer's disease.
 14. A method according to claim 12, wherein the disorder is senile dementia.
 15. A method according to claim 11, wherein the disorder is peripheral neuropathy.
 16. A method according to claim 11, wherein the disorder is a nerve injury.
 17. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim
 4. 18. A method according to claim 17, wherein the disorder is a dementing disorder.
 19. A method according to claim 18, wherein the disorder is Alzheimer's disease.
 20. A method according to claim 18, wherein the disorder is senile dementia.
 21. A method according to claim 17, wherein the disorder is peripheral neuropathy.
 22. A method according to claim 17, wherein the disorder is a nerve injury.
 23. A method of treating a mammal having a neurodegenerative or neurological disorder of the central or peripheral nervous system, which comprises administering to said mammal a therapeutically effective amount of a compound according to claim
 7. 24. A method according to claim 23, wherein the disorder is a dementing disorder.
 25. A method according to claim 24, wherein the disorder is Alzheimer's disease.
 26. A method according to claim 24, wherein the disorder is senile dementia.
 27. A method according to claim 23, wherein the disorder is peripheral neuropathy.
 28. A method according to claim 23, wherein the disorder is a nerve injury. 